11Department of Pediatrics, Ibaraki Prefectural University of Health Sciences Hospital, 4733 Ami, Ami-cho, Inashiki-gun, Ibaraki, Japan 300-0331
2Center of Medical science, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-cho, Inashiki-gun, Ibaraki, Japan 300-0394
33Department of Pediatrics, Matsudo clinic, 1-3, Nakai-cho, Matsudo, Chiba 270-2242
Submission: August 10, 2023; Published: August 23, 2023
*Corresponding author: Tomohiro Nakayama, Center of Medical science, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-cho, Inashiki-gun, Ibaraki, Japan 300-0394
How to cite this article: Tomohiro Nakayama*, Saki Saeki, Naoko Nakayama, Haruka Ooguro, Junko Nakayama, Hiroshi Maruyama and Nobuaki Iwasaki. Effects of Levetiracetam on Childhood-onset Refractory Epilepsy Classified by Level of
Intellectual Disability. Open Access J Neurol Neurosurg 2023; 18(3): 555988. DOI: 10.19080/OAJNN.2023.18.555988.
The efficacy of levetiracetam (LEV) for childhood-onset refractory epilepsy was retrospectively evaluated from medical records, based on the level of intellectual disability. The study sample included 84 patients (68 adults, 16 children) with childhood- onset refractory epilepsy who had been treated with LEV (dose: adult, 1000 mg/day; children, 30 mg/kg/day) for approximately 1.7 years. The responder rates (≥ 50% and ≥ 75% reduction in seizure frequency from baseline) were 85.7% and 42.9% for focal seizures in adults with normal intelligence; the responder rates for focal seizures in adults with intellectual disabilities were average 69.0% and 6.9%, respectively. Serious adverse events were not observed. A high level (≧75%) of reduction can be expected for focal seizures in adults with normal intelligence but cannot be expected in adults with intellectual disabilities. Further studies are required to investigate these.
Refractory epilepsy is a condition in which seizures do not stop despite treatment with two or three more appropriate antiepileptic drugs for at least two years, with the patient’s daily life interrupted, accounting for 20-30% of all patients with epilepsy . Recently, new antiepileptic drugs, such as gabapentin (July 2006), topiramate (TPM) (August 2007), lamotrigine (LTG) (December 2008), and levetiracetam (LEV) (September 2010) have been approved in Japan. These drugs are expected to be superior to existing drugs in terms of ease of use due to fewer drug interactions  and are increasingly used as additional treatments for refractory epilepsy.
LEV has been reported to be highly effective in the treatment of refractory epilepsy, with seizure reduction rates of 50% or greater ranging between 25-74% [3-7] and complete seizure suppression rates of 6–38% [3-5,8]. In our previous study of 162 patients with childhood-onset refractory epilepsy at our institution, the rates of seizure reduction of ≥ 50% were 51.1% in adults and 44.0% in children, and the rate of complete seizure suppression was
0.0% in both groups. Although the maintenance dose may not be sufficient, the seizure reduction rate of 50% or more was as high as previously reported; however, the complete seizure control rate was lower than that reported in previous studies.
Many patients with intellectual and physical disabilities attend our institution. On this premise, we hypothesized that the severity of intellectual and physical impairment contributes to the lower efficacy of LEV. Therefore, we planned to study the efficacy of LEV in the treatment of childhood-onset refractory epilepsy by first selecting a group of patients who received a relatively high dose of LEV and secondarily based on the level of intellectual and physical impairment.
From September 2010 to August 2013, 187 patients (100 males and 87 females) were treated with LEV at the Department of Pediatrics, Ibaraki Prefectural University of Health Sciences Hospital, and Matsudo Clinic. The subjects were patients with childhood-onset refractory epilepsy who were eligible for followup.
Before its approval for use in children in Japan, we explained
to the patients and their parents that LEV had already been
approved for use in children overseas who have partial seizures
or generalized seizures. LEV was used in children in Japan after
gaining approval in May 2013. Among these patients, those who
were 16 years of age or older at the start of LEV prescription were
classified as adults and those younger than 16 years of age were
classified as children.
Sixty-eight adults (34 males and 34 females) and 16 children
(8 males and 8 females) were selected from the adult and
pediatric groups, respectively, who received LEV of 1,000 mg/
day or more in the adult group and 30 mg/kg/day or more per
body weight in the pediatric group. The patient background
included the number of antiepileptic drugs, LEV initial dose,
LEV maintenance dose, and LEV maintenance dose per body
weight. The percentage of seizure frequency reduction (≥50%
and ≥75%) from baseline was retrospectively classified into focal
and generalized seizures based on the 2010 proposed revision of
the International Classification of Epileptic Seizure Types. Before
introducing LEV, baseline seizure frequency was calculated from
the 6 month average seizure frequency. Next, we examined the
rate of seizure frequency reduction using intelligence quotient
classification (based on the Tanaka-Binet test), gross motor
function classification system (GMFCS) level, and motor paralysis
site. The changes in seizure frequency were evaluated at the
following five levels: 1. 100% seizure frequency reduction; 2.75-
99% seizure frequency reduction; 3. 50-74% seizure frequency
reduction; 4. 25-49% seizure frequency reduction; and 5.0-24%
seizure frequency reduction.
This study was approved by the Ethics Committee of Ibaraki
Prefectural University of Health Sciences. The cases at the Matsudo
Clinic were reviewed by the university on behalf of the authors.
Approval for off-label use was obtained from the Ethics Committee
of the Ibaraki Prefectural University of Health Sciences.
The starting age of LEV prescription was 33.9±10.3 years
old in adults and 9.3±3.8 years old in children. The number of
antiepileptic drugs used was 4.6±1.2 in adults and 4.3±0.8 in
children. The mean duration of treatment was 20.5±9.1 months in
adults and 20.3±13.0 months in children. The initial dose of LEV
was 430± 220 mg/day in adults and 270± 170 mg/day, 11.0± 6.9
mg/kg/day in children, and the maintenance doses were 1500±
570 mg/day in adults and 1250± 530 mg/day in children. The
maintenance dose per body weight was 27±13 mg/kg/day in
adults and 51±14 mg/kg/day in children.
The 50% or greater seizure frequency reduction rates were
73.5% and 43.8% in adults and children, respectively, and the
75% or greater reduction rates were 11.8% and 6.3% in adults
and children, respectively (Figure 1). The seizure frequency
reduction rates classified according to intellectual disability in
adults are shown in Table 1. In adults with normal intelligence, the
rates of ≥50% and ≥75% reduction in focal seizures were 85.7%
and 42.9%, respectively. The rate of ≥75% seizure reduction was
higher than that in the other groups. In adults with intellectual
disabilities, ≥50% and ≥75% seizure reduction in focal seizures
were average 69.0%, ranging from 50.0% to 85.7%, and average
6.9%, ranging from 0% to 14.3%, respectively. Statistical analysis
was not performed due to the insufficient number of the patients.
The rates of ≥50% and ≥75% seizure reduction for generalized
seizures in adults and for both focal and generalized seizures in
children varied, and there was no clear trend in the rates in each
group (data not shown). The seizure frequency reduction rates
classified by the GMFCS level and motor paralysis (no paralysis,
hemiplegia, paraplegia, and tetraplegia) were not significantly
different between the groups (data not shown).
Adverse effects included somnolence, drowsiness, irritability,
headache, insomnia, decreased vitality, itchy skin, and wandering
in adults, and increased arousal and somnolence in children. No
significant or new drug reactions were observed.
LEV is assumed to exert anticonvulsant effects by acting on
synaptic vesicle protein 2A (SV2A) in neurons. It is classified as a
second-generation antiepileptic drug and its mechanism of action
is completely different from that of conventional antiepileptic
drugs. It does not mediate P450 hepatic cytochrome metabolism
and does not interact with other drugs . It is expected to be
effective for myoclonus epilepsy because its structure is similar to
that of piracetam, a drug used to treat myoclonus ; however,
it was found to be effective as a treatment for partial seizures in
children and adults worldwide. In Japan, the drug was approved
for the treatment of partial seizures in children in May 2013,
and monotherapy became available in February 2015. It is now
widely used clinically. The seizure reduction rate of 50% or
more for refractory epilepsy is 25-74% [4- 7], and the complete
seizure suppression rate is as high as 6-38% [4-8]. The efficacy
of LEV for myoclonic seizures in Lennox-Gastaut syndrome
, Dravet syndrome , and epileptic encephalopathy with
continuous spike-and-wave during sleep wave [13,14] has been
On the other hand, a multicenter network study of antiepileptic
medicine reported that LEV is the most commonly used
antiepileptic drug but is also the most frequently discontinued
drug , suggesting that there may be many cases in which the
efficacy is not as good as expected.
In this study, we investigated the efficacy of LEV on seizure
frequency in a relatively high-dose group. Although the rate of
seizure frequency reduction of 50% or more was as high as that
previously reported, the rate of complete seizure suppression was
0%, and the rate of seizure frequency reduction of 75% or more
was relatively low, ranging from 6.3 to 11.8%. In addition, when
the results were re-evaluated by intellectual disability, the rate of
50% or more seizure reduction rate in adults with focal seizures
in both the normal and retarded intelligence groups was as high
as previously reported, but the rate of 75% or more seizure
reduction rate was high only in the normal intelligence group. Opp
et al.  reported that intellectual disability was associated with
limited efficacy and discontinuation of LEV, which is consistent
with the results of the present study.
In the present study, we also followed the patients for a long
period, averaging 1.7 years (20 months). Although the initial
effect was significant in the early stage, the seizure suppression
rate decreased from 50% to 19% after 1 year , and the initial
effect may have diminished.
In conclusion, LEV can be expected to be effective for the
treatment of focal refractory childhood-onset epilepsy with 75%
or greater seizure reduction in the mentally normal adult group.
However, maintaining 75% or greater seizure control for a long
time in many patients with intellectual disabilities is difficult,
even if LEV is initially effective. Further investigation is needed
to determine the efficacy of LEV classified by level of intellectual